I. Carbostyrils
Carbostyril derivatives represented by the following general formula (1), and salts thereof: ##STR1## wherein R is a benzoyl group which may optionally have lower alkoxy groups on the phenyl ring as substituents and the carbon-carbon bond in the 3 and 4 positions of the carbostyril skeleton is a single bond or double bond,
are well-known in the art (U.S. Pat. No. 4,415,572, which is incorporated by reference herein in its entirety).
These carbostyrils have been found to be useful as an oral inotropic agent for treatment of patients with congestive heart failure (U.S. Pat. No. 4,415,572; and Hori et al, Jpn. Circ. J., 50:659-666 (1986)). Several studies have demonstrated that the above carbostyrils improve hemodynamic indexes, and exercise capacity in congestive heart failure patients (Inoue et al, Heart Vessels, 2:166-171 (1986); Sasayama et al, Heart Vessels, 2:23-28 (1986); and Feldman et al, Am. Heart J., 116:771-777 (1988)). In addition, multi-center randomized placebo-controlled trials both in Japan and in the United States demonstrated that these carbostyrils improve both quality of life and reduced the risk of death in patients with congestive heart failure (OPC-8212 Multicenter Research Group, Cardiovasc. Drugs Ther., 4:419-425 (1990); Feldman et al, Am. J. Cardiol., 68:1203-1210 (1991); and Feldman et al, N. Engl. J. Med., 329:149-155 (1993)).
The mechanisms of action associated with the inotropic properties of these carbostyrils include a decrease in potassium current (Iijima et al, J. Pharmacol. Exp. Ther., 240:657-662 (1987)), a mild inhibition of phosphodiesterase, and an increase in the inward calcium current (Yatani et al, J. Cardiovasc. Pharmacol., 13:812-819 (1989); and Taira et al, Arzneimittelforschung, 4:347-355 (1984)). However, the dose of the carbostyrils which was most effective in reducing mortality (60 mg daily) showed no or little hemodynamic effect, implying that the drug may reduce mortality through another mechanism, rather than its positive inotropic effect (Feldman et al, . N. Engl. J. Med., 329:149-155 (1993); and Packer, N. Engl. J. Med., 329:201-202 (1993)).
The above carbostyrils are also known to inhibit the production of various cytokines, including TNF-.alpha. and IL-6, by lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMC) in a dose-dependent manner (Maruyama et al, Biochem. Biophys. Res. Commu., 195:1264-1271 (1993); and Matsumori et al, Circul., 89:955-958 (1994)).
Moreover, they can induce a reversible neutropenia associated with a decrease in CFU-C (Feldman et al, Am. Heart J., 11 :771-777 (1988); OPC-8212 Multicenter Research Group, Cardiovasc. Drugs, Ther., 4:419-425 (1990); Feldman et al, Am. J. Cardiol, 68:1203-1210 (1991); and Feldman et al, N. Endl J. Med., 329.:149-155 (1993)).
Additionally, the above carbostyrils have been found to be useful in regulating apoptosis (programmed cell death), and in the treatment of cancer, inhibition of tumor metastasis and inhibition of RNA virus replication (U.S. patent application Ser. No. 07/989,028, filed Apr. 30, 1993, which corresponds to European Patent Publication 0552373, each of which is incorporated by reference herein in their entirety; Nakai et al, Jpn. J. Cancer Res., Abstract, and Proc. Jpn. Cancer Assoc., page 581 (1993); and Maruyama et al, Biochem. Biophys Res. Comm., 195:1264-1271 (1993)).
It has been surprising to find in the present invention that these carbostyrils, particularly the species 3,4-dihydro-6- 4-(3,4-dimethoxybenzoyl)-1-piperazinyl!-2(1H)-quinoline (hereinafter "vesnarinone"), inhibit nucleoside and nucleobase transport in mammalian cells, as the structures of these compounds are entirely different from the structure of known compounds which inhibit nucleoside and nucleobase transport.